Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.

Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jκ), a key effector of canonical Notch signaling endowed with intrinsic transcription-repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung. Increased CSL levels enhanced the proliferative potential of HKCs and SCC cells, while silencing of CSL induced growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels gave rise to rapidly expanding tumors, while cells with silenced CSL formed smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKCs and SCC cells with silenced CSL revealed major modulation of apoptotic, cell-cycle, and proinflammatory genes. We also show that the histone demethylase KDM6B is a direct CSL-negative target, with inverse roles of CSL in HKC and SCC proliferative capacity, tumorigenesis, and tumor-associated inflammatory reaction. CSL/KDM6B protein expression could be used as a biomarker of SCC development and indicator of cancer treatment

Genetic and Environmental Influences on Semantic Verbal Fluency Across Midlife and Later Life

Despite the relevance of semantic fluency measures to risk for dementia and psychiatric disorders, little is known about their genetic and environmental architecture in mid-to-late life. Participants represent 21,684 middle-aged and older adult twins (M = 60.84 years, SD = 11.21; Range 40-89) from six studies from three countries participating in the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium. All completed the same measure of semantic fluency (naming animals in 60 seconds). Results revealed small-to-moderate phenotypic associations with age and education, with education more strongly and positively associated with fluency performance in females than males. Heritability and environmental influences did not vary by age. Environmental variance was smaller with higher levels of education, but this effect was observed only in males. This is the largest study to examine the genetic and environmental architecture of semantic fluency, and the first to demonstrate that environmental influences vary based on levels of education

Underdiagnosis of mild cognitive impairment: A consequence of ignoring practice effects

INTRODUCTION: Longitudinal testing is necessary to accurately measure cognitive change. However, repeated testing is susceptible to practice effects, which may obscure true cognitive decline and delay detection of mild cognitive impairment (MCI). METHODS: We retested 995 late-middle-aged men in a ∼6-year follow-up of the Vietnam Era Twin Study of Aging. In addition, 170 age-matched replacements were tested for the first time at study wave 2. Group differences were used to calculate practice effects after controlling for attrition effects. MCI diagnoses were generated from practice-adjusted scores. RESULTS: There were significant practice effects on most cognitive domains. Conversion to MCI doubled after correcting for practice effects, from 4.5% to 9%. Importantly, practice effects were present although there were declines in uncorrected scores. DISCUSSION: Accounting for practice effects is critical to early detection of MCI. Declines, when lower than expected, can still indicate practice effects. Replacement participants are needed for accurately assessing disease progression.Published versio

Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Influence of young adult cognitive ability and additional education on later-life cognition

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation-namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area (n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.Peer reviewe

Associations Between MRI-Assessed Locus Coeruleus Integrity and Cortical Gray Matter Microstructure

The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer's disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62-71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes

Changes in the Frontotemporal Cortex and Cognitive Correlates in First-Episode Psychosis

Background: Loss of cortical volume in frontotemporal regions has been reported in patients with schizophrenia and their relatives. Cortical area and thickness are determined by different genetic processes, and measuring these parameters separately may clarify disturbances in corticogenesis relevant to schizophrenia. Our study also explored clinical and cognitive correlates of these parameters.Methods: Thirty-seven patients with first-episode psychosis (34 schizophrenia, 3 schizoaffective disorder) and 38 healthy control subjects matched for age and sex took part in the study. Imaging was performed on an magnetic resonance imaging 1.5-T scanner. Area and thickness of the frontotemporal cortex were measured using a surface-based morphometry method (Freesurfer). All subjects underwent neuropsychologic testing that included measures of premorbid and current IQ, working and verbal memory, and executive function.Results: Reductions in cortical area, more marked in the temporal cortex, were present in patients. Overall frontotemporal cortical thickness did not differ between groups, although regional thinning of the right superior temporal region was observed in patients. There was a significant association of both premorbid IQ and IQ at disease onset with area, but not thickness, of the frontotemporal cortex, and working memory span was associated with area of the frontal cortex. These associations remained significant when only patients with schizophrenia were considered.Conclusions: Our results suggest an early disruption of corticogenesis in schizophrenia, although the effect of subsequent environmental factors cannot be excluded. In addition, cortical abnormalities are subject to regional variations and differ from those present in neurodegenerative diseases

Agent orange exposure and prostate cancer risk in the million veteran program

BackgroundThe US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk.Patients and methodsParticipants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.Results and interpretationOn univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09, &lt;10-6) but not with metastatic PCa (HR: 1.07, 95% CI: 0.98-1.15, p = 0.10) or PCa death (HR: 1.02, 95% CI: 0.83-1.23, p = 0.09). Similar results were found when accounting for genetic risk. Agent Orange exposure history may not improve modern PCa risk stratification